Alzheimer's disease

Forgetfulness is the typical symptom early in the course of AD. It first affects declarative information, primarily “episodic” events, but also “semantic” content which has been experienced and learned, and which can – if remembered – easily be expressed in words (Tulving, Reference Tulving2002). A necessary prerequisite for explicit recall is the capability to learn, i.e. to obtain, understand and memorize information, and therefore an intact apparatus for the processing of declarative information (Takashima et al., Reference Takashima2006). Bottleneck structures of this apparatus in the medio-temporal lobe, entorhinal region and hippocampus are affected by Alzheimer-type plaque and neurofibrillary changes early in the course of this degenerative process (van Hoesen and Hyman, Reference van Hoesen and Hyman1990; Scahill et al., Reference Scahill2002). Therefore the learning of new information is impaired and these difficulties increase with ongoing neurodegeneration. During this process the intraneuronal neurofibrillary changes are far more focused on the structures of the temporal lobe responsible for declarative memory formation and retrieval than the widespread plaque pathology (Braak and Braak, Reference Braak and Braak1991). Activities of daily living are first impaired by an anterograde amnesia, which can also be verified by neuropsychological tests: from the onset of the first clinical symptoms most patients find it increasingly hard to keep track of what is going on, which leads to problems remembering events which have happened in the recent past, while remote history is usually well retained and accessible. After a longer course of illness with more intense and distributed brain changes, learning difficulties become more severe and include salient new events; remembering past events proves harder and other skills are also affected.

Several secondary deficits can be understood as logical consequences of amnesia (Harwood et al., Reference Harwood, Barker, Ownby and Duara2000). These include problems with temporal and spatial orientation, a process which relies on constant updates of what was intended and what has happened. This unsettling uncertainty of who (why, what, where, when) has done (become, happened, etc.) may cause anxiety, agitation and aggression (Förstl et al., Reference Förstl1993a; Reference Förstl1994). The patients' attempts at the best possible interpretation of this subjectively inexplicable experience can lead to delusional reasoning and to even greater cognitive and emotional turmoil. In advanced stages of AD, the access to large parts of the autobiographical memory are lost that normally provide personal continuity and the identity of the self (Levine, Reference Levine2004; Moscovitch et al., Reference Moscovitch2005). In emotional moments with focused attention, patients may become briefly aware of their lost past and personhood.

Familiar caregivers are not always recognized and must find a non-confronting style of comforting communication, which is preferably not based on spoken words, as they – if understood at all – would immediately be forgotten. Caregivers may find it difficult to cope with such declarative deficits during the early stage of dementia, but usually develop an appropriate understanding of the patients' main memory deficits in due course.

Dementia with Lewy bodies

A combination of Parkinson's and Alzheimer-type pathology may lead to a “dementia with Lewy bodies” (DLB) (McKeith et al., Reference McKeith2004; Perneczky et al., Reference Perneczky2007). Lewy bodies are the pathological hallmarks of Parkinson's disease just as plaques and tangles are the characteristics of AD. Clinically these patients suffer from the combination of a dementia syndrome together with recurring confusional states (Förstl et al., Reference Förstl1993b).

A confusional state can be considered as turbulence of the “stream of consciousness” (James, Reference James1890). One aspect of this stream of consciousness, the perception of the present, of the “moment”, is short-term-memory. When testing verbal or visual material, human short-term-memory covers around seven to eights seconds and seven to eight items. Outside critical situations and psychological laboratories, moments pulsating through our consciousness may be slightly shorter and hold less information (Pöppel, Reference Pöppel1997). When alert and attentive, humans can understand a complicated sentence with several clauses or reflect perceptions and intentions of several other individuals within a larger group. Language is one prominent attempt at making moments last. It can be compared with a “replay function,” which allows performers and listeners to repeat, learn and share experience. But all of these reflections take their own time, and the mirrors are never so well aligned that they can reflect one moment without distortion. Seemingly authentic recurrences of past events are infrequent and no sign of mental health (Aziz and Warner, Reference Aziz and Warner2005).

This stream of consciousness, with its big, “conscious” pictures usually accompanied by a running commentary and its minute minimal sensations (Leibniz, Reference Leibniz and Latta1714), corresponds to the momentary electrochemical oscillation of the whole brain. It includes the feeling, filtering, amplifying, comparing and eventually selecting of information most relevant to be attended to, and eventually even to be learned.

The decisive pharmacological deficit in DLB is a lack of the neurotransmitter acetylcholine, which is synthesized in the basal nucleus of Meynert (Perry et al., Reference Perry, Walker, Grace and Perry1999). This strategically important brainstem nucleus is affected not only by Alzheimer pathology but also by Lewy body pathology. Wakefulness, attention, filtering and learning are all critically dependent on acetylcholine, which in large parts of the brain can only be received from the basal nucleus. Acetylcholine improves attention and working memory performance (Furey et al., Reference Furey2000). Without acetylcholine, there is no “laminar” stream of consciousness, but disturbed vigilance, nightmares, and certainly no organized storage or retrieval of relevant information. Confusional states may initially manifest as disturbances of sleeping and dreaming, but do not usually cease after opening the eyes (Galanikis et al., Reference Galanikis2001). Patients will not usually remember explicitly what has happened during a confusional state, whereas caregivers will not easily forget such dramatic behavioral disturbances.

Frontotemporal degeneration

This neurodegenerative process, which is rarer than AD, affects the prefrontal cortex and frontal poles of the temporal lobes (Neary et al., Reference Neary1998; Johnson et al., Reference Johnson2005). They represent the phylogenetically youngest regions of the human neocortex dedicated to resolving interpersonal exchanges and taking care of one's future (Okuda et al., Reference Okuda2003). A large part of the brain's computational capacity is continuously devoted to controlling and improving social skills (Sodian et al., Reference Sodian2005). Sociobiologists discredit such perfectionist intentions of refining cooperation as attempts to improve the balance between our personal investment and benefit quite egotistically (Trivers, Reference Trivers1971). A vast fronto-dorsal cortico-subcortical circuit contributes to efforts usually summarized as intelligence (Alexander et al., Reference Alexander, Crutcher and Delong1990), its fronto-orbital counterpart deals with questions addressing reason, and the medial circuit produces behaviors generally associated with (free) will. Intelligence, or reason, or will are lost when these circuits are damaged selectively. If they collaborate in an intact brain, they achieve insight into complex social situations called “theory of mind” (Stone et al., Reference Stone, Baron-Cohen and Knight1998). The anterior paracingulate, superior temporal sulcus and bilateral anterior temporal poles are prominently involved in this complex task (Gallagher and Frith, Reference Gallagher and Frith2003), and they are predominantly affected in FTD. This “theory of mind” or “mentalizing” is the ability to see things from a different perspective, to understand how others view my actions, how they feel about it and will probably react to my potential actions (Buckner and Carroll, Reference Buckner and Carroll2006). Careful planning, taking others' actual views and collective experience accumulated over time into account means that an individual need not undergo every painful experience himself/herself. Imagining the potential consequences of one's intentions leads, more frequently than not, to inhibition, to refraining from certain actions.

Patients with FTD lose interest in many areas that require them to make a bit of an effort, but they do not shy away from faux pas (Gregory et al., Reference Gregory2002; Sturm et al., Reference Sturm, Rosen, Allison, Miller and Levenson2006). This loss of interest, of respect, and apathy toward the effect that one's actions may have, can occasionally lead to petty crime and rarely to more severe and fatal violations of social conventions (Diehl et al., Reference Diehl2006). These social deficits are associated with a lack of self-awareness (Eslinger et al., Reference Eslinger2005). On account of their “inability to will” and their lack of insight, these patients cannot be held responsible for what they have or have not done. This complete disintegration of future perspective and motivation in the course of the illness is usually accompanied by a loss of interest in the individual's personal past and basically in everything else (Diehl-Schmid et al., Reference Diehl-Schmid2006; Matuszewski et al., Reference Matuszewski2006). The patients' apathy or disinhibition, agitation and awkward behavior causes more caregiver distress than is observed with AD (de Vugt et al., Reference de Vugt2006), particularly because it appears almost incomprehensible that patients retain their knowledge and skills without hardly ever employing them.